Ziprasidone, chemically named (5-[2-{4-(1,2-benzisothiazol-3-yl)piperizin-1-yl}ethyl]-6-chlorooxindole)hydrochloride hydrate, is a substituted benzisothiazolylpiperazine. The free base of ziprasidone has the following structure:
Ziprasidone and some of its uses are described by U.S. Pat. Nos. 4,831,031 and 5,312,925.
Like clozapine and risperidone, ziprasidone is a highly potent and selective 5-HT2 receptor and dopamine D2 receptor antagonist. Seeger, T. F. et al., J. Pharmacol. Exp. Ther., 275(1):101–113 (1995). Ziprasidone is characterized as an antipsychotic, but may also have anxiolytic and antidepressant effects due to its ability to inhibit serotonin and noradrenaline reuptake. Davis, R. and Markham, A., CNS Drugs, 8(2):154–159 (1997). The therapeutic potential of ziprasidone may also be enhanced by its high affinity for the 5-HT1A, 5-HT1D, 5-HT2C receptor subtypes. Seeger, T. F. et al., J. Pharmacol. Exp. Ther., 275(1):101–113 (1995).
The metabolism of ziprasidone is complex. When administered orally to healthy humans, the drug is extensively metabolized by at least four major pathways: 1) N-dealkylation of the ethyl side chain attached to the piperazinyl nitrogen; 2) oxidation at sulfur resulting in the formation of sulfoxide or sulfone; 3) reductive cleavage of the bensisothiazole moiety; and 4) hydration of the C═N bond and subsequent sulfur oxidation or N-dearylation of the benzisothiazole moiety. Prakash, C. et al., Drug Metab. Dispos., 25(7):863–872 (1997). At least 12 human metabolites have been identified: ziprasidone sulfoxide (ZIP-SO); ziprasidone sulfone (ZIP-SO2); 3-(piperazine-1-yl)-1,2-benzisothiazole (BITP); BITP sulfoxide; BITP sulfone; 6-chloro-5-(2-piperazin-1-yl-ethyl)-1,3-dihydroindol-2-one; 6-chloro-5-(2-{4-[imino-(2-mercapto-phenyl)methyl]-piperazin-1-yl}ethyl)-1,3-dihydro-indol-2-one; 6-chloro-5-(2-{4-[imino-(2-methylsulfanyl-phenyl)methyl]-piperazin-1-yl} ethyl)-1,3-dihydro-indol-2-one; S-methyl-dihydro-ziprasidone; S-methyl-dihydro-ziprasidone sulfoxide; dihydro-ziprasidone sulfoxide; and (6-chloro-2-oxo-2,3-dihydro-1H-indol-5-yl)acetic acid. Two metabolites, ZIP-SO and ZIP-SO2, both of which are formed by oxidation of the ziprasidone sulfur atom are discussed herein. These metabolites have the following structures:
Both ZIP-SO and ZIP-SO2 are minor metabolites, and account for less than about 10% and less than about 3% of ziprasidone metabolites found in human urine, respectively. Prakash, C. et al., Drug Metab. Dispos., 25(7):863–872 (1997). It has been reported that neither metabolite likely contributes to the antipsychotic activity of ziprasidone. Prakash, C. et al., Drug Metab. Dispos., 25(7):863–872 (1997). Indeed, it has been reported that ziprasidone metabolites in general are not active at the D2 and 5-HT2A receptor sites. Ereshefsky, L., J. Clin. Psych., 57(suppl. 11):12–25 (1996).
Ziprasidone offers a number of benefits, but unfortunately many adverse effects are associated with its administration. Examples of adverse affects of ziprasidone include, but are not limited to, nausea, somnolence, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular disturbances, male sexual dysfunction, and elevated serum liver enzyme levels. Davis, R. and Markham, A., CNS Drugs, 8(2):154–159 (1997). These adverse effects can significantly limit the dose level, frequency, and duration of drug therapy. It is thus desirable to find a compound which possesses advantages of ziprasidone but fewer of its disadvantages.